Direct acting CB1 agonists have been used for the treatment or prevention of neurological and psychiatric disorders associated with endocannabinoid dysfunction and diseases in which the CB1 subtype of cannabinoid receptor is involved. However, they suffer from disadvantages such as addiction, abuse potential as well as tolerance associated with their use.
Anorexia nervosa (AN) is a major psychiatric eating disorder associated with substantial morbidity and mortality and its characteristic symptoms include the refusal to maintain a minimally normal body weight, an intense fear of becoming fat, and a disturbed perception of body shape and size. It is also characterized by anhedonia whereby patients experience little pleasure or reward in many aspects of their lives. Pharmacotherapeutic interventions for treatment of AN are extremely limited, as there is still a lack of understanding of their pathogenesis. The endocannabinoid system has been recently recognized as an important target in both reward processing and feeding behavior. Studies in AN patients have linked AN associated disorder attitudes and behavior to a dysfunctional endocannabinoid system. In recently concluded studies, THC, a cannabinoid receptor agonist was shown to attenuate weight loss in a rodent model of activity-based anorexia. Although use of a direct-acting CB1 receptor agonist for treating AN associated anhedonia and weight loss seems an attractive pharmacotherapeutic approach, its use may lead to addiction.
Accomplishing CB1 agonism with a different pharmacological mechanism may represent a safer alternative. One promising alternative approach is the development of positive allosteric modulators (PAMs) of CB1 receptors which, by binding to a sub-type-specific and topographically distinct site from the orthosteric pocket, would potentiate the action of endocannabinoids and thus act more selectively to tune CB signaling in a site- and event-specific fashion.
Highly CB1 selective modulators with a minimal propensity to produce adverse effects would be desirable. Moreover, it would be desirable to identify types of modulators which are brain-permeable, functionally potent modulators (cAMP) and likely devoid of abuse potential.